Protein malnutrition early in life increased apoptosis but did not alter the ß-cell mass during gestation.

We evaluated whether early-life protein restriction alters structural parameters that affect ß-cell mass on the 15th day and 20th day of gestation in control pregnant (CP), control non-pregnant (CNP), low-protein pregnant (LPP) and low-protein non-pregnant (LPNP) rats from the fetal to the adult life stage as well as in protein-restricted rats that recovered after weaning (recovered pregnant (RP) and recovered non-pregnant). On the 15th day of gestation, the CNP group had a higher proportion of smaller islets, whereas the CP group exhibited a higher proportion of islets larger than the median. The ß-cell mass was lower in the low-protein group than that in the recovered and control groups. Gestation increased the ß-cell mass, ß-cell proliferation frequency and neogenesis frequency independently of the nutritional status. The apoptosis frequency was increased in the recovered groups compared with that in the other groups. On the 20th day of gestation, a higher proportion of islets smaller than the median was observed in the non-pregnant groups, whereas a higher proportion of islets larger than the median was observed in the RP, LPP and CP groups. ß-Cell mass was lower in the low-protein group than that in the recovered and control groups, regardless of the physiological status. The ß-cell proliferation frequency was lower, whereas the apoptosis rate was higher in recovered rats compared with those in the low-protein and control rats. Thus, protein malnutrition early in life did not alter the mass of ß-cells, especially in the first two-thirds of gestation, despite the increase in apoptosis.

Protein restriction during pregnancy impairs intra-islet GLP-1 and the expansion of ß-cell mass.

We evaluated whether protein restriction during pregnancy alters the morphometry of pancreatic islets, the intra-islet glucagon-like peptide-1 (GLP-1) production, and the anti-apoptotic signalling pathway modulated by GLP-1. Control non-pregnant (CNP) and control pregnant (CP) rats were fed a 17% protein diet, and low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) groups were fed a 6% protein diet. The masses of islets and ß-cells were similar in the LPNP group and the CNP group but were higher in the CP group than in the CNP group and were equal in the LPP group and the LPNP group. Both variables were lower in the LPP group than in the CP group. Prohormone convertase 2 and GLP-1 fluorescence in α-cells was lower in the low-protein groups than in the control groups. The least PC2/glucagon colocalization was observed in the LPP group, and the most was observed in the CP group. There was less prohormone convertase 1/3/glucagon colocalization in the LPP group than in the CP group. GLP-1/glucagon colocalization was similar in the LPP, CP and CNP groups, which showed less GLP-1/glucagon colocalization than the LPNP group. The mRNA Pka, Creb and Pdx-1 contents were higher in islets from pregnant rats than in islets from non-pregnant rats. Protein restriction during pregnancy impaired the mass of ß-cells and the intra-islet GLP-1 production but did not interfere with the transcription of genes of the anti-apoptotic signalling pathway modulated by GLP-1.

Early protein restriction increases intra-islet GLP-1 production and pancreatic ß-cell proliferation mediated by the ß-catenin pathway.

PURPOSE: In the present study, we investigated whether intra-islet GLP-1 production and its modulation have a role in apoptosis, proliferation or neogenesis that is compromised by protein restriction during the foetal and suckling periods. METHODS: Exendin-4, a GLP-1 receptor agonist (treated groups), or saline (non-treated groups) was intraperitoneally administered for 15 days from 75 to 90 days of age in female adult rats consisting of offspring born to and suckled by mothers fed a control diet (control groups) and who had the same diet until 90 days of age or offspring born to and suckled by mothers fed a low-protein diet and who were fed the control diet after weaning until 90 days of age (protein-restricted group). RESULTS: The ß-cell mass was lower in the protein-restricted groups than in the control groups. Exendin-4 increased ß-cell mass, regardless of the mother's protein intake. The colocalization of GLP-1/glucagon was higher in the protein-restricted rats than in control rats in both the exendin-4-treated and non-treated groups. The frequency of cleaved caspase-3-labelled cells was higher in the non-treated protein-restricted group than in the non-treated control group and was similar in the treated protein-restricted and treated control groups. Regardless of treatment with exendin-4, Ki67-labelled cell frequency and ß-catenin/DAPI colocalization were elevated in the protein-restricted groups. Exendin-4 increased the area of endocrine cell clusters and ß-catenin/DAPI and FoxO1/DAPI colocalization regardless of the mother's protein intake. CONCLUSIONS: Protein restriction in early life increased intra-islet GLP-1 production and ß-cell proliferation, possibly mediated by the ß-catenin pathway.